title: Small-Molecule targeting of translation initiation for cancer therapy.
abstract: Translation initiation plays a critical role in the regulation of cell growth and tumorigenesis. We report here that inhibiting translation initiation through induction of eIF2α phosphorylation by small-molecular-weight compounds restricts the availability of the eIF2.GTP.Met-tRNAi ternary complex and abrogates the proliferation of cancer cells in vitro and tumor growth in vivo. Restricting the availability of the ternary complex preferentially down-regulates the expression of growth-promoting proteins and up-regulates the expression of ER stress response genes in cancer cells as well as in tumors excised from either animal models of human cancer or cancer patients. These findings provide the first direct evidence for translational control of gene-specific expression by small molecules in vivo and indicate that translation initiation factors are bona fide targets for development of mechanism-specific anti-cancer agents.
authors.affiliation: Department of Medicine, Brigham and Women's Hospital, Boston.
authors.forename: Bertal H
authors.initials: BH
authors.lastname: Aktas
authors.forename: Yuan
authors.initials: Y
authors.lastname: Qiao
authors.forename: Esra
authors.initials: E
authors.lastname: Ozdelen
authors.forename: Roland
authors.initials: R
authors.lastname: Schubert
authors.forename: Sema
authors.initials: S
authors.lastname: Sevinc
authors.forename: Fred
authors.initials: F
authors.lastname: Harbinski
authors.forename: Luciano
authors.initials: L
authors.lastname: Grubissich
authors.forename: Samuel
authors.initials: S
authors.lastname: Singer
authors.forename: Jose A
authors.initials: JA
authors.lastname: Halperin
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002839:Chromans / Q000494:pharmacology*; D003022:Clotrimazole / Q000494:pharmacology*; D019938:Cyclin D1 / Q000096:biosynthesis; D004195:Disease Models, Animal; D015118:Eicosapentaenoic Acid / Q000494:pharmacology*; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D005260:Female; D006801:Humans; D051379:Mice; D008811:Mice, Inbred DBA; D010442:Peptide Chain Initiation, Translational / Q000187:drug effects*; D010766:Phosphorylation / Q000187:drug effects; D014176:Protein Biosynthesis; D011897:Random Allocation; D045162:Thiazolidinediones / Q000494:pharmacology*; D000077288:Troglitazone; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D002839:Chromans; D015852:Eukaryotic Initiation Factor-2; D045162:Thiazolidinediones; D019938:Cyclin D1; D015118:Eicosapentaenoic Acid; D003022:Clotrimazole; D000077288:Troglitazone